Ataxia Telangiectasia (AT) is a genetic disorder that surprisingly manifests itself only in certain tissues. This tissue preference is especially relevant to the AT-affected CNS, in which degeneration of the cerebellar cortex and subsequently many of its afferent and efferent neuronal pathways are the major target site for pathology. The obvious loss of Purkinje neurons that is a hallmark of the disease has resulted in studies that mainly focus on the role of ATM in this neuronal population with considerable less attention paid to the glial compartment. While the functional loss of ATM might affect the survival of neuronal populations directly, it is becoming increasingly evident that many defined neurological disorders are caused by glial deficiencies, especially in the astrocyte compartment, which then indirectly affect the survival of surrounding neuronal components. In an attempt to determine whether and to what extend astrocytes contribute to the pathology observed in AT, we isolated astrocytes from homozygous ATM deficient mouse brains and compared them to their wildtype controls. Astrocytes isolated from cerebellar tissue, the major site of human pathology, were highly oxidized, had a decreased ability to mount an anti-oxidant response and showed deregulation of the glutamate transporter GLAST in a tissue and age specific manner. These functional changes suggest that the mutant astrocyte population is likely to be significantly impaired in the ability to maintain a protective environment for neighboring cells. The deregulation of the glutamate transporter GLAST seems particular significant as the cerebellum contains a disproportionate ratio of glutaminergic neurons that rely on proper glutamate homeostasis controlled by astrocytes. Interestingly, the impairment of mutant astrocytes was not global but region specific and our preliminary results show that astrocytes isolated from cortical tissue of the same animals did not differ from wildtype controls in the tested parameters. This finding is consistent with the human pathology in which cerebellar functions are most severely and progressively affected by the disease. Taken together, our observations lead to the hypothesis that astrocytes contribute to the pathological phenotype of the cerebellum in AT. To test this hypothesis we will induce loss of AT function in specific CNS cell populations in vivo and determine the contribution of specific mutant cell types to the neurodegeneration in the cerebellum. Currently available animal models are not suitable to conduct this research due to premature cell death and global loss of AT function. In addition, we will determine whether there is a critical window of vulnerability during which the deficiency in AT leads to impairment of function in astrocytes. PUBLIC HEALTH RELEVANCE: The aim of this proposal is to establish the role of astrocytes in Ataxia Telangiectasia (AT). Based on our preliminary studies we suggest that astrocytes play a major role in the pathology and we show a cerebellar specific impairment of astrocyte function that is consistent with the human pathology. To characterize the consequence of this impairment in the astrocyte compartment in the absence of the cancer development that severely restricts the lifespan of existing AT knockout animals, we propose to generate CNS tissue specific inducible AT mutant animals that develop a CNS pathology similar to the human patients and with a live span that allows us to characterize the role of astrocytes in the disease progression.